U.S. patent number 3,962,248 [Application Number 05/553,142] was granted by the patent office on 1976-06-08 for process for making 11-piperazino-diazepines, oxazepines, thiazepines and azepines.
This patent grant is currently assigned to Sandoz, Inc.. Invention is credited to Josef Schneider.
United States Patent |
3,962,248 |
Schneider |
June 8, 1976 |
**Please see images for:
( Certificate of Correction ) ** |
Process for making 11-piperazino-diazepines, oxazepines,
thiazepines and azepines
Abstract
This invention concerns a novel process for the preparation of
6-piperazinyl derivatives of morphantridine and corresponding
ring-substituted and hereto analogues thereof, comprising reacting
a compound of the formula: ##SPC1## Wherein A is benzene or
thiophene, and X is --CH.sub.2 -- or a hetero atom or group, with a
complex comprising titanium, zirconium, hafnium or vanadium and a
corresponding piperazinyl derivative. The end products are in
general known and useful as neuroleptics.
Inventors: |
Schneider; Josef (Minusio,
CH) |
Assignee: |
Sandoz, Inc. (Hanover,
NJ)
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Family
ID: |
27428831 |
Appl.
No.: |
05/553,142 |
Filed: |
February 26, 1975 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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346343 |
Mar 29, 1973 |
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Foreign Application Priority Data
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Apr 4, 1972 [CH] |
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4898/72 |
Apr 4, 1972 [CH] |
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4901/72 |
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Current U.S.
Class: |
540/548; 540/551;
540/557; 540/587 |
Current CPC
Class: |
C07D
295/03 (20130101); C07D 333/20 (20130101); C07D
333/32 (20130101); C07D 513/04 (20130101) |
Current International
Class: |
C07D
513/04 (20060101); C07D 513/00 (20060101); C07D
333/32 (20060101); C07D 333/00 (20060101); C07D
295/00 (20060101); C07D 333/20 (20060101); C07D
295/03 (20060101); C07D 403/04 (); C07D 413/04 ();
C07D 417/04 () |
Field of
Search: |
;260/268TR |
Other References
white et al., J. Org. Chem., vol. 32, pp. 213-214, (1967). .
Weingarten et al., J. Org. Chem., vol. 32, pp. 3246-3249, (1967).
.
Fryer et al., J. Organic Chemistry, vol. 34, pp. 1143-1145,
(1969)..
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Primary Examiner: Rollins; Alton D.
Assistant Examiner: Tovar; Jose
Attorney, Agent or Firm: Sharkin; Gerald D. Honor; Robert S.
McGovern; Thomas O.
Parent Case Text
This is a continuation of application Ser. No. 346,343 filed Mar.
29, 1973, now abandoned.
Claims
What is claimed is:
1. A process for the production of a compound of formula I,
##SPC6##
wherein
R.sub.1 is hydrogen, alkoxyalkyl of 2 to 6 carbon atoms in the
aggregate thereof, alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1
to 4 carbon atoms, or alkanoyl-oxalkyl of 3 to 22 carbon atoms in
the aggregate thereof,
R.sub.4 is hydrogen, alkyl, alkoxy or alkylthio, wherein the alkyl
groups have 1 to 4 carbon atoms, halogen, or trifluoromethyl,
and
a. A is ##SPC7##
wherein R.sub.2 is hydrogen, alkyl, dialkylaminosulphonyl,
alkylsulphonyl, wherein the alkyl groups have 1 to 4 carbon atoms,
alkoxy or alkylthio of 1 to 4 carbon atoms, halogen, nitro,
trifluoromethylsulphonyl, trifluoromethoxy, trifluoromethylthio,
acetyl, cyano or trifluoromethyl, and
R.sub.3 is hydrogen, halogen or alkyl of 1 to 4 carbon atoms,
and
X is --CH.sub.2 --, --O--, --S--, --NH or --N-alkyl wherein the
alkyl group has 1 to 3 carbon atoms, or
b. A is ##SPC8##
and X is --CH.sub.2 -- or --S--, which comprises reacting a
compound of formula II, ##SPC9##
wherein X, A and R.sub.4 are as defined above, with a metal-amine
complex wherein the metal is titanium, zirconium, hafnium or
vanadium, and the amine is a compound of formula III, ##SPC10##
wherein R.sub.1 is as defined above.
2. A process according to claim 1, in which the metal-amine complex
is formed by reacting a tetrachloride or tetrabromide of the metal
with a compound of formula III.
3. A process according to claim 2, in which the mol ratio of metal
tetrachloride or tetrabromide to compound of formula III is about
1:4.
4. A process according to claim 1, carried out in the presence of a
tertiary amine as an acid-binding agent, the mol ratio of the
tertiary amine to metal-amine complex being at least 2:1.
5. A process according to claim 1, wherein R.sub.1 is hydroxyalkyl
of 1 to 4 carbon atoms, and the reaction is carried out in the
presence of a large amount of solvent in the presence of at least a
ten fold excess of a tertiary amine over the metal-amine
complex.
6. A process according to claim 1, carried out in the presence of
chlorobenzene, toluene or anisole, as solvent.
7. A process according to claim 1, carried out at a temperature
form 20.degree. to 150.degree.C.
8. A process according to claim 1, wherein R.sub.3 is hydrogen.
Description
IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS
The present invention relates to a new process for the production
of compounds of formula I, ##SPC2##
wherein
R.sub.1 is hydrogen, alkoxyalkyl of 2 to 6 carbon atoms in the
aggregate thereof, alkyl of 1 to 4 carbon atoms, hydroxyalkyl of 1
to 4 carbon atoms, or acyloxyalkyl of 3 to 22 carbon atoms in the
aggregate thereof,
R.sub.4 is hydrogen, alkyl, alkoxy or alkylthio, wherein the alkyl
groups have 1 to 4 carbon atoms, halogen, or trifluoromethyl,
and
A signifies the structure ##SPC3##
A. WHEN A denotes Z1, X is a --CH.sub.2, --O--, --S--, --NH or
--N--alkyl group wherein the alkyl group has 1 to 3 carbon
atoms,
R.sub.2 is hydrogen, alkyl, dialkylamino-sulphonyl, alkylsulphonyl,
wherein the alkyl groups have 1 to 4 carbon atoms, alkoxy or
alkylthio of 1 to 4 carbon atoms, halogen, nitro,
trifluoromethylsulphonyl, trifluoromethoxy, trifluoromethylthio,
acetyl, cyano or trifluoromethyl, and
R.sub.3 is hydrogen, halogen or alkyl of 1 to 4 carbon atoms,
or
B. WHEN A denotes Z2, X is a --CH.sub.2 --or --S--group.
In the substituents R.sub.2, R.sub.3 and R.sub.4 halogen preferably
denotes chlorine or bromine, especially chlorine. When the
hydroxyalkyl group of the substituent R.sub.1 is acylated, the acyl
group preferably contains at most 18 carbon atoms, especially at
most 10 carbon atoms. The acyl group is preferably aliphatic and
may be saturated or unsaturated.
In accordance with the invention a compound of formula I may be
obtained by a process comprising reacting a compound of formula II,
##SPC4##
wherein X, A and R.sub.4 are as defined above, with a metal-amine
complex comprising titanium, zirconium, hafnium or vanadium, and a
compound of formula III, ##SPC5##
wherein R.sub.1 is as defined above.
A resulting compound of formula I wherein R.sub.1 is acyloxyalkyl
may be saponified to produce a compound of formula I wherein
R.sub.1 is hydroxyalkyl. A resulting compound of formula I wherein
R.sub.1 is hydroxyalkyl may be esterified to produce a compound of
formula I wherein R.sub.1 is acyloxyalkyl.
One preferred method of effecting the process of the invention
comprises reacting a compound of formula II with a metal-amine
complex in the presence of an acid-binding agent. A tertiary amine,
e.g. triethylamine, pyridine, dimethyl-aniline or an excess of a
compound of formula III may be used as acid-binding agent. At least
one mol, preferably, however, two mols of the acid-binding amino
compound should be used, calculated on one mol of metal-amine
complex.
The reaction is conveniently effected in an organic solvent, e.g.
an aromatic solvent such as toluene, a halogenated aromatic solvent
such as chlorobenzene, a halogenated aliphatic solvent such as
dichloroethane, or preferably an ether such as anisole. The
reaction temperature is not critical within wide limits, and is
conveniently from 20.degree.C to 150.degree.C, preferably from
50.degree. to 120.degree.C.
The metal-amine complex used for the reaction of the invention is
preferably obtained by reaction of a halide, preferably the
tetrachloride or tetrabromide of titanium, zirconium, hafnium or
vanadium, with a compound of formula III, conveniently at a mol
ratio of 1:4 respectively. The reaction is conveniently effected in
the solvent subsequently used for the reaction between a compound
of formula II and the metal-amine complex. The metal halide may be
used in the form of a soluble (mono- or di) etherate thereof,
preferably the anisole dietherate.
It is preferred to use titanium and zirconium and especially
titanium.
After the reaction, the compound of formula I may be isolated in
conventional manner. The largely insoluble metal compounds present
in the reaction mixture may be conveniently removed by conversion
into soluble form by the addition of an alcohol, e.g. isopropanol,
and by subsequent precipitation by the addition of aqueous ammonia.
The compounds of formula I, obtained in accordance with the
invention, may be isolated in known manner for example by
crystallization from the reaction mixture from which metal
compounds have been removed, after concentrating the reaction
mixture, and may be subsequently purified in known manner, e.g. by
re-crystallization from isopropanol.
When a compound of formula I wherein R.sub.1 is hydroxyalkyl is
produced, the reaction product may be obtained in colloidal form,
since the hydroxyalkyl group can also react with the metal halide
with ester formation. In order to avoid the appearance of too much
gelatinous material, which could disturb the course of the
reaction, it is convenient to effect the reaction in the presence
of a large amount of solvent, e.g. chlorobenzene or anisole,
preferably in the presence of an excess (10- to 20-fold molar
excess) of a tert.amine, e.g. triethylamine.
A compound of formula I wherein R.sub.1 is hydroxyalkyl may
alternatively be obtained by alkaline saponification of a compound
of formula I wherein R.sub.1 is an acylated hydroxyalkyl group,
e.g. with a dilute sodium hydroxide solution.
The esterification of a compound of formula I wherein R.sub.1 is
hydroxyalkyl may be effected in known manner, e.g. with a reactive
acid derivative, e.g. a halide of a corresponding acid, in a
solvent such as chloroform, conveniently in the presence of an
acid-binding agent such as triethylamine, at room temperature.
Free base forms of the compounds of formula I produced in
accordance with the invention may be converted into their acid
addition salt forms in conventional manner and vice versa. Examples
of suitable salts are the hydrochlorides, hydrobromides, sulphates,
fumarates, maleates and p-toluenesulphonates.
The compounds of formula II, used as starting materials in the
process according to the invention, are known or may be produced
according to known methods or according to methods described in the
Examples hereafter for the production of
10H-thieno[3,2-c][1]benzazepines, or according to methods analogous
to any of these methods.
The compounds of formula III, used as starting materials in the
process according to the invention are known or may be prepared
according to known methods or according to methods described in the
Examples hereafter for the production of 1-tert-butylpiperazine, or
according to methods analogous to any of these methods.
For example a compound of formula III wherein R.sub.1 is
acyloxyalkyl may be obtained by reacting N-benzylpiperazine with a
halo- alcohol, esterifying the hydroxy group of the
N-benzyl-N'-hydroxy-piperazine with a reactive acid derivative,
e.g. a halide, especially the chloride of a corresponding acid, and
subsequently removing the benzyl group from the resulting compound
hydrogenolytically.
Compounds of formula I produced in accordance with the present
invention are in general known, and have been described in the
literature.
The compounds of formula I are useful because they possess
pharmacological activity in animals. In particular the compounds
are useful as neuroleptics as indicated by a suppression of
locomotor activity in mice on p.o. administration of 0.1 to 5 mg/kg
animal body weight of the compounds, in accordance with the method
of Caviezel and Baillod, described in Pharm. Acta Helv. 33, 465-484
(1958).
For the above-mentioned use, the dosage to be administered will
naturally vary depending on the compound used, the mode of
administration and the treatment desired. However, in general,
satisfactory results are obtained when administered at a daily
dosage of from about 0.01 mg to about 10 mg per kg animal body
weight, conveniently given in divided doses 2 to 4 times a day or
in sustained release form. For the larger mammals, the total daily
dosage is in the range from about 1 to about 500 mg, and dosage
forms suitable for oral administration comprise from about 0.25 mg
to about 250 mg of the compound admixed with a solid or liquid
pharmaceutical carrier or diluent.
The compounds of formula I may be administered in pharmaceutically
acceptable acid addition salt form. Such acid addition salt forms
exhibit the same order of activity as the free base forms and are
readily prepared in conventional manner. Representative acid
addition salt forms include organic acid salt forms such as the
maleate, fumarate and tartrate and mineral acid salt forms such as
the hydrochloride, hydrobromide and sulphate. A pharmaceutical
composition may comprise a compound of formula I, in free base form
or in pharmaceutically acceptable acid addition salt form, in
association with a pharmaceutical carrier or diluent. Such
compositions may be prepared by conventional techniques to be in
the form of, for example, capsules, tablets, suspensions or
solutions, for enteral or parenteral administration. Aside from the
usual pharmaceutical diluents or carriers, e.g. water, alcohol,
talc, stearic acid, natural or hardened oils and waxes, these
pharmaceutical compositions may contain suitable preserving,
stabilizing, wetting, solubilizing, sweetening, flavouring or
colouring agents.
In the general formula I, when A denotes Z1, the substituent
R.sub.2 is preferably in the 2 or 3 position, the substituent
R.sub.3 is preferably in the 4 position, and when A denotes Z1 and
Z2, the substituent R.sub.4 is preferably in the position 7 or 8,
i.e. meta or para to the group or atom X.
In the following non-limitative Examples all temperatures are
indicated in degrees Centigrade, room temperature is a temperature
between 20.degree. and 30.degree.C, unless otherwise indicated.
EXAMPLE 1
8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine
840 cc of toluene, 90 cc of anisole and 79.2 g of titanium
tetrachloride are introduced, at room temperature, in a 2.5 liter
sulphonating flask provided with a dropping funnel, reflux
condenser and thermometer, whereby a dark brown, clear solution is
formed. A mixture of 167 g of N-methyl piperazine and 100 cc of
toluene is added thereto while cooling externally with water,
whereby the temperature rises to 50.degree.-55.degree. and the
amine complex, in finely divided form, forms a beige to dark brown
coloured suspension. 102 g of
8-chloro-10,11-dihydro-11-oxo-5H-dibenzo[b,e][1,4]-diazepine and 83
g of N-methyl piperazine are subsequently added, and the reaction
mixture is heated to the boil (110.degree.-112.degree.) for 3 hours
while stirring. Cooling is then effected to 60.degree.-70.degree.,
125 cc of isopropanol are added, whereby the insoluble titanium
compounds formed during the reaction again dissolve. After the
addition of 8 g of diatomaceous earth and subsequently 115 cc of
concentrated ammonia (about 27%), cooling is effected to about
30.degree. while stirring and the resulting precipitate is filtered
off. The filter residue is washed with 2-3 330 cc portions of
toluene. The filtrate is subsequently mixed with water, and the
organic phase is extracted with dilute, approx. 10% hydrochloric
acid. The base is precipitated by the dropwise addition of the
hydrochloric acid extract to an excess of dilute ammonia. The
precipitate is taken up in ether, the ether solution is washed with
water and dried over sodium sulphate. After removal of the ether by
evaporation and recrystallization from isopropanol,
8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo-[b,e][1,4]dia
zepine, having a M.P. of 184.degree.-185.degree., is obtained.
EXAMPLE 2
6-(4-tert-butyl-1-piperazinyl)-morphantridine
840 cc of toluene, 90 cc of anisole and 93.5 g of zirconium
tetrachloride are introduced at room temperature in a 2.5 liter
sulphonating flask provided with a dropping funnel, reflux
condenser and thermometer, whereby a dark brown, clear solution is
formed. A mixture of 248 g of N-tert-butyl piperazine and 100 cc of
toluene is added thereto while cooling externally with water,
whereby the temperature rises to 50.degree.-55.degree. and the
amine complex, in finely divided form, forms a dark brown coloured
suspension. 87 g of morphantridin-6-one and 123.5 g of N-tert-butyl
piperazine are subsequently added and the reaction mixture is
heated to the boil (110.degree.-112.degree.) for 3 hours while
stirring. Cooling is then effected to 60.degree.-70.degree., 125 cc
of isopropanol are added, whereby the insoluble zirconium compounds
formed during the reaction again dissolve. After the addition of 8
g of diatomaceous earth and subsequently 115 cc of concentrated
ammonia (approx. 27%) cooling is effected to about 30.degree. while
stirring and the resulting precipitate is filtered off. The filter
residue is washed with 2-3 330 cc portions of toluene. The filtrate
is subsequently mixed with water and the organic phase is extracted
with dilute, approx. 10% hydrochloric acid. The base is
precipitated by the dropwise addition of the hydrochloric acid
extract to an excess of dilute ammonia. The precipitate is
subsequently taken up in ether, the ether solution is washed with
water and dried over sodium sulphate. After removing the ether by
evaporation, the residue is dissolved in acetone and 38 g of maleic
acid are added to the solution. The solution is subsequently
concentrated, ethyl acetate and some ether are added and the
resulting precipitate is filtered off. After recrystallization from
acetone/ethyl acetate/ether, the resulting
6-(4-tert-butyl-1-piperazinyl)-morphantridine maleate has a M.P. of
138.degree.-141.degree..
The 1-tert-butyl piperazine, used as starting material in the above
process, may be produced as follows:
1. 1-benzyl-4-tert-butyl piperazine
A solution of 2000 g of bis-(2-chloroethyl)-tert-butylamine in 500
cc of ethanol and a solution of 1095 g of benzylamine in 750 cc of
ethanol are simultaneously added dropwise to 1000 cc of boiling
ethanol. After the addition is complete, the reaction mixture is
heated to the boil for 1 hour. The mixture is subsequently
concentrated in a vacuum and the residue is dissolved in dilute
hydrochloric acid. The acid solution is washed with ether and is
subsequently rendered alkaline with a concentrated, aqueous sodium
hydroxide solution. The liberated base is extracted with ether and
the ether residue is distilled. 1-benzyl-4-tert-butyl piperazine
has a B.P. of 160.degree.-162.degree. at 12 mm of Hg.
2. 1-tert-butyl piperazine
348.5 g of 1-benzyl-4-tert-butyl piperazine are dissolved in 1200
cc of 99% ethanol and 10 g of a 5% palladium/charcoal catalyst are
added to the resulting solution. The solution is subsequently
shaken in a hydrogenation apparatus, in a hydrogen atmosphere (1
atmosphere) and at room temperature, until the take up of hydrogen
is complete. Filtration is subsequently effected, the filtrate is
concentrated by evaporation in a vacuum and the residue is
distilled in a vacuum. 1-tert-butyl piperazine is obtained in the
form of a colourless oil, having a B.P. of 66.degree.-70.degree. at
12 mm of Hg, which crystallizes upon standing. The crystals have a
M.P. of 35.degree.-40.degree..
By using the processes described in the above Examples 1 and 2 and
the corresponding starting materials, the following compounds may
be obtained in analogous manner:
5-methyl-11-(4-methyl-1-piperazinyl)-dibenzo[b,e][1,4]-diazepine,
having a M.P. of 122.degree.-124.degree. (from ether/petroleum
ether),
2-chloro-11-(4-methyl-1-piperazinyl)-dibenzo[b,f][1,4]-thiazepine,
having a M.P. of 116.degree.-120.degree. (from ether/petroleum
ether),
6-(4-methyl-1-piperazinyl)-merphantridine, having a M.P. of
138.degree.-139.degree. (from acetone/petroleum ether),
2-methyl-11-(4-methyl-1-piperazinyl)-dibenzo[b,f][1,4]-thiazepine,
having a M.P. of 99.degree.-107.degree. (from petroleum ether),
2-chloro-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]-oxazepine,
having a M.P. of 104.degree.-110.degree. (from petroleum
ether),
2-bromo-11-(4-methyl-1-piperazinyl)-dibenzo[b,f][1,4]-thiazepine,
having a M.P. of 138.degree.-139.degree. (from acetone/petroleum
ether),
2-nitro-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepine,
having a M.P. of 192.degree.-193.degree. (from
chloroform/acetone/petroleum ether),
2-dimethylaminosulphonyl-11-(4-methyl-1-piperazinyl)-dibenzo[b,f][1,4]thiaz
epine, having a M.P. of 192-193.degree. (from acetone/petroleum
ether),
2-dimethylaminosulphonyl-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxazep
ine, having a M.P. of 149.degree.-150.degree. (from ether/petroleum
ether),
2-methylsulphonyl-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepine,
having a M.P. of 178.degree.-179.degree. (from
acetone/ether/petroleum ether),
2-trifluoromethoxy-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepine
dihydrochloride monohydrate, having a M.P. of 200-210.degree. (from
alcohol/ether),
7-chloro-4-(4-methyl-1-piperazinyl)-thieno[2,3-b][1,5]-benzothiazepine,
having a M.P. of 162.degree.-164.degree. (from ethyl acetate),
2-trifluoromethylsulphonyl-11-(4-methyl-1-piperazinyl)-dibenzo[b,f][1,4thia
zepine, having a M.P. of 168.degree.-170.degree. (from
ether/petroleum ether),
2-acetyl-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]-oxazepine,
having a M.P. of 116.degree.-118.degree. (from acetone/petroleum
ether),
2-trifluoromethyl-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepine,
the fumarate thereof having a M.P. of 214.degree.-216.degree. (from
acetone/petroleum ether),
2-trifluoromethylsulphonyl-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxaz
epine, having a M.P. of 120.degree.-122.degree. (from
ether/petroleum ether),
2-methylsulphonyl-11-(4-ethyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepine,
having a M.P. of 190.degree.-191.degree. (from acetone/petroleum
ether),
4-(4-methyl-1-piperazinyl)-thieno[2,3-b][1,5]benzothiazepine,
having a M.P. of 112.degree.-114.degree. (from absolute
ethanol).
4-(4-methyl-1-piperazinyl)-10H-thieno[3,2-c][1]-benzazepine, having
a M.P. of 145.degree.-147.degree. (from ether/petroleum ether),
8-chloro-4-(1-piperazinyl)-10H-thieno[3,2-c][1]-benzazepine, having
a M.P. of 80.degree.-100.degree. (from acetone/water in the
presence of charcoal),
8-chloro-4-[4-(2-acetoxyethyl)-1-piperazinyl]-10H-thieno[3,2-c][1]benzazepi
ne, having a M.P. of 185.degree.-189.degree. (from ether/petroleum
ether),
8-chloro-4-(4-methyl-1-piperazinyl)-10H-thieno-[3,2-c][1]benzazepine,
having a M.P. of 193.degree.-195.degree. (from acetone/petroleum
ether),
2-methylthio-11-(4-methyl-1-piperazinyl)-dibenz-[b,f][1,4]oxazepine,
having a M.P. of 198.degree.-201.degree. (maleate),
4-(4-tert-butyl-1-piperazinyl)-10H-thieno[3,2-C][1]-benzazepine,
having a M.P. of 147.degree.-176.degree. (maleate),
7-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[3,2-c][1]benzazepine,
having a M.P. of 180.degree.-181.degree. (from acetone/petroleum
ether),
7-chloro-4-(4-methyl-1-piperazinyl)-10H-thieno-[3,2-c][1]benzazepine,
having a M.P. of 184.degree.-185.degree. (from acetone),
7-chloro-4-(4-.beta.-hydroxyethyl-1-piperazinyl)-10H-thieno[3,2-c][1]benzaz
epine, having a M.P. of 192.degree.-194.degree. (from ethyl
acetate),
8-chloro-4-(4-.beta.-hydroxyethyl-1-piperazinyl-10H-thieno[3,2-c][1]benzaze
pine, having a M.P. of 202.degree.-203.degree. (from ethyl
acetate),
2-trifluoromethylsulphonyl-11-[4-(.beta.-pentanoyloxyethyl)-1-piperazinyl]-
dibenz[b,f][1,4]oxazepine, the oxalate thereof having a M.P. of
213.degree.-216.degree.,
2-trifluoromethylsulphonyl-11-(4-.beta.-hydroxyethyl-1-piperazinyl)-dibenz[
b,f][1,4]oxazepine, having a M.P. of 121.degree.-123.degree. (from
ether/petroleum ether),
2-trifluoromethylsulphonyl-11-(1-piperazinyl)-dibenz[b,f][1,4]oxazepine,
having a M.P. of 183-186.degree. (from ether),
2-trifluoromethylsulphonyl-11-(4-.beta.-hydroxypropyl-1-piperazinyl)-dibenz
[b,f][1,4]oxazepine, having a M.P. of 132.degree.-134.degree. (from
ether/petroleum ether),
2-trifluoromethylthio-11-(4-.beta.-hydroxyethyl-1-piperazinyl)-dibenz[b,f][
1,4]oxazepine, having a M.P. of 121.degree.-123.degree. (from
petroleum ether),
2-trifluoromethylsulphonyl-11-(4-.beta.-oleyloxyethyl-1-piperazinyl)dibenz[
b,f][1,4]oxazepine (oil with an Rf value=0.88 [silicagel SL 254
Antec]to using chloroform/cyclohexane/diethyl amine (5:4:1) as
eluant and Dragendorff's reagent as detection agent),
1,4-dimethyl-11-(4-methyl-1-piperazinyl)-dibenz-[b,f][1,4]oxazepine,
having a M.P. of 143.degree.-144.degree. (from ether/petroleum
ether),
3,4-dimethyl-11-(4-methyl-1-piperazinyl)-dibenz-[b,f][1,4]oxazepine,
having a M.P. of 167.degree.-169.degree. (from acetone/petroleum
ether),
2,8-dichloro-11-(4-methyl-1-piperazinyl)-dibenz-[b,f][1,4]oxazepine,
having a M.P. of 130.degree.-131.degree. (from acetone/petroleum
ether),
4,8-dichloro-11-(4-methyl-1-piperazinyl)-dibenz-[b,f][1,4]oxazepine,
having a M.P. of 134.degree.-135.degree. (from acetone/petroleum
ether),
4-methyl-8-chloro-11-(4-methyl-1-piperazinyl)-dibenz-[b,f][1,4]oxazepine,
having a M.P. of 150.degree.-151.degree. (from ether/petroleum
ether),
4-methyl-7-chloro-11-(4-methyl-1-piperazinyl)-dibenz-[b,f][1,4]oxazepine,
having a M.P. of 167.degree.-168.degree. (from acetone/petroleum
ether),
2,4-dichloro-11-(4-methyl-1-piperazinyl)-dibenz-[b,f][1,4]oxazepine,
having a M.P. of 135.degree.-138.degree. (from acetone/petroleum
ether),
2-chloro-11-(1-piperazinyl)-debenz[b,f][1,4]oxazepine, having a
M.P. of 178.degree.-180.degree. (from acetone/petroleum ether).
The starting materials for the production of
10H-thieno[3,2-c][1]benzazepines may be obtained as follows:
4,5-dihydro-10H-thieno[3,2-c][1]benzazepin-4-one
14.8 g of 2-(2-amino-phenyl)-thienone, 23.8 g of solid potassium
hydroxide and 19.6 g of hydrazine hydrate are heated to the boil at
reflux in 180 cc of diethylene glycol for 3 hours. After diluting
the reaction mixture with ice water, extraction is effected with
ether. The ether phase is washed thrice with water, dried over
sodium sulphate and concentrated. 2-(2-aminobenzyl)-thiophene is
obtained in the form of a light yellow oil having a B.P. of
128.degree.-130.degree. at 0.1 mm of Hg.
46 cc of a 20% solution of phosgene in toluene are added dropwise
at -3.degree., with stirring, to a solution of 9.8 g of the product
obtained above in 60 cc of toluene. The reaction mixture is
subsequently allowed to warm to room temperature while passing
through a stream of phosgene, and is then heated to the boil at
reflux for half an hour. After driving out the excess phosgene with
a stream of nitrogen, the reaction mixture is concentrated in a
vacuum and the residue is distilled. 10.8 g of
2-(2-isocyanato-benzyl)-thiophene, having a B.P. of 108.degree. at
0.05 mm of Hg, are obtained.
10.5 g of 2-(2-isocyanato-benzyl)-thiophene (B.P. 108.degree./0.05
mm of Hg) are heated to 110.degree. with 105 g of polyphosphoric
acid for 1 hour while stirring. The reaction mixture is
subsequently rendered alkaline with a concentrated ammonia solution
while cooling internally and externally with ice and the resulting
precipitate is filtered off. This is washed with water, dried and
crystallized from acetone while treating with charcoal.
4,5-dihydro-10H-thieno[3,2-c][1]benzazepin-4-one is obtained in the
form of grains having a M.P. of 225.degree.-236.degree. (between
150.degree. and 200.degree. conversion into bright needles).
8-chloro- or
7-chloro-4,5-dihydro-10H-thieno[3,2-c][1]benzazepin-4-one
6 g of N-p-toluenesulphonyl-5-chloro or 4-chloro)-anthranilic acid
are heated to the boil at reflux with 10 cc of thionyl chloride for
11/2 hours. After evaporating to dryness in a vacuum, the residue
is recrystallized from methylene chloride/petroleum ether. The
resulting N-p-toluenesulphonyl-5-chloro-anthranilic acid chloride
has a M.P. of 134.degree.-136.degree.,
N-p-toluenesulphonyl-4-chloro-anthranilic acid chloride has a M.P.
of 135.degree.-140.degree..
A solution of 6 g of stannic chloride in 10 cc of carbon disulphide
is slowly added dropwise at the boil, under reflux, to a mixture of
7 g of finely pulverized N-p-toluenesulphonyl-5-chloro (or
4-chloro)-anthranilic acid chloride and 3.4 g of thiophene in 25 cc
of carbon disulphide. After the addition is complete, stirring is
effected at room temperature for 2 hours. The solvent is
subsequently evaporated in a vacuum, the residue is treated with
ice water and hydrochloric acid and extracted with ethyl acetate.
The ethyl acetate extract is washed with 2N hydrochloric acid,
water and a saturated aqueous potassium bicarbonate solution, is
dried with sodium sulphate and concentrated. The evaporation
residue is divided between ether and a 1 normal aqueous sodium
hydroxide solution. The aqueous alkaline solution is acidified with
concentrated hydrochloric acid and the resulting precipitate is
drawn off by suction. The suction filter residue is washed with
water and recrystallized from ethyl acetate/petroleum ether.
2-(2-p-toluenesulphonamido-5-chloro-phenyl)-thienone has a M.P. of
164.degree.-167.degree., 2-(2-p-toluenesulphonamide-4
-chloro-phenyl)-thienone has a M.P. of 140.degree.-141.degree..
8.4 g of 2-(2-p-toluenesulphonamido-5-chloro (or
4-chloro)-phenyl)-thienone are stirred at room temperature with 100
cc of concentrated sulphuric acid for 4 hours. The reaction product
is subsequently poured on ice and the resulting mixture is rendered
alkaline with a concentrated aqueous sodium hydroxide solution
while cooling. A precipitate is obtained, which is taken up in
ether. The ether solution is washed with water, dried with sodium
sulphate and concentrated, whereby a residue is obtained. After
recrystallization from ether/petroleum ether in the presence of
charcoal and aluminium oxide, 2-(2-amino-5-chloro-phenyl)-thienone
has a M.P. of 97.degree.-98.degree. and
2-(2-amino-4-chloro-phenyl)-thienone has a M.P. of
66.degree.-72.degree..
15.5 g of 2-(2-amino-5-chloro (or 4-chloro)-phenyl)-thienone, 23.8
g of solid potassium hydroxide and 19.6 g of hydrazine hydrate are
heated to the boil at reflux in 180 cc of diethylene glycol for 2
hours. After diluting the reaction mixture with ice water,
extraction is effected with ether. The ether phase is washed thrice
with water, dried with sodium sulphate and concentrated.
2-(2-amino-5-chloro-benzyl)-thiophene, having a B.P. of
150.degree.-157.degree. at 0.1 mm of Hg, and
2-(2-amino-4-chloro-benzyl)-thiophene, having a B.P. of
137.degree.-140.degree. at 0.05 mm of Hg, are obtained in the form
of an oil.
46 cc of a 20 % solution of phosgene in toluene are added dropwise
at -3.degree., while stirring, to a solution of 11 g of
2-(2-amino-5-chloro (or 4-chloro)-benzyl)-thiophene in 60 cc of
toluene. The reaction mixture is subsequently allowed to warm to
room temperature while introducing a stream of phosgene and is
subsequently heated to the boil at reflux for half an hour. After
driving off the excess phosgene with a nitrogen stream, the
reaction mixture is concentrated in a vacuum and the residue is
distilled. 2-(2-isocyanato-5-chloro-benzyl)-thiophene, having a
B.P. of 137.degree.-139.degree. at 0.1 mm of Hg, and
2-(2-isocyanato-4-chloro-benzyl)-thiophene, having a B.P. of
124.degree.-125.degree. at 0.05 mm of Hg, are obtained.
Ring closure of 2-(2-isocyanato-5-chloro (or
4-chloro)-benzyl)-thiophene, using the process described above with
respect to 2-(2-isocyanatobenzyl)thiophene, yields
8-chloro-4,5-dihydro-10H-thieno[3,2-c][1]benzazepin-4-one, having a
M.P. of 280.degree.-281.degree. (after recrystallization from
dioxane/acetone), and
7-chloro-4,5-dihydro-10H-thieno[3,2-c][1]benzazepin-4-one, having a
M.P. of 264.degree.-266.degree. (after recrystallization from
acetone).
Following the procedure described in Example 1 or 2 but replacing
the starting materials with appropriate compounds in equivalent
amounts, the following compounds are prepared:
2-methoxy-11-(4-methyl-1-piperazinyl)dibenz [b,f][1,4]-oxazepine;
2-fluoro-11-(4-methyl-1-piperazinyl)dibenz-[b,f][1,4]oxazepine;
2-cyano-11-(4-methyl-1-piperazinyl)dibenz-[b,f][1,4]oxazepine;
2,4-difluoro-11-(4methyl-1-piperazinyl)dibenz-[b,f][1,4]oxazepine;
2,4-dibromo-11-(4-methyl-1-piperazinyl)dibenz-[b,f][1,4]oxazepine;
8-methoxy-11-(4-methyl-1-piperazinyl)dibenzo-[b,f][1,4]thiazepine;
7-methylthio-11-(4-methyl-1-piperazinyl)dibenzo-[b,f][1,4]thiazepine;
8-fluoro-11-(4-methyl-1-piperazinyl)dibenz-[b,f][1,4]oxazepine;
8-bromo-11-(4-methyl-1-piperazinyl)dibenz-[b,f][1,4]oxazepine;
8-trifluoromethyl-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine
; and
2-nitro-11-(4.beta.-methoxyethyl-1-piperazinyl)dibenz-[b,f][1,4]oxazepine.
* * * * *